Abstract
BackgroundThe human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known.Methods/Principal FindingsWe studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels.Conclusions/SignificanceThe coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia.
Highlights
QKI protein is a member of the STAR (Signal Transduction and Activation of RNA) family [1]
All three QKI proteins are highly expressed in all glial cells in mice, including oligodendrocytes and astrocytes [14], which are the most abundant glial cells in the brain [15]
Astrocyte glioma cells were treated with three different pools of small interference RNA (siRNA) designed to silence all QKI splice variants (QKI-tot), or only splice variant QKI-5 or QKI-7 (Fig. 1A)
Summary
QKI protein is a member of the STAR (Signal Transduction and Activation of RNA) family [1] This family of proteins contains an RNA binding domain called KH [2]. QKI has been proposed as a candidate gene for schizophrenia after several lines of evidence including linkage analysis [5,6] and mRNA expression studies [6,7,8]. The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is highly expressed in astrocytes, but its function in these cells is not known
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